Although increasing animal evidence supports the hypothesis that in utero exposure to endocrine disrupting compounds can have a long-term impact on the health of the 2nd and subsequent generations, the evidence in humans is nearly non-existent. In addition, individuals may have differences in susceptibility to chemical exposure based on their genetic make-up. We propose to study genetic susceptibility in a unique population of children whose mothers, participants of the Seveso Women's Health Study (SWHS), were exposed to one of the most potent endocrine disruptors, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). On July 10, 1976, an explosion at a chemical plant near Seveso, Italy resulted in a toxic plume that exposed nearby residents to high levels of TCDD. The SWHS, a retrospective cohort study, was initiated in 1996, to investigate the health of 981 women who were newborn to age 40 years in 1976, had resided in the immediate vicinity of the plant, and had archived samples of blood collected soon after the explosion. The SWHS is the only comprehensive study of health effects of TCDD exposure in a female population, and has the unique benefit of measurements of individual-level TCDD in blood collected near the time of the explosion. We are currently re-contacting SWHS women to enroll ~955 children aged 0-38 years in a study of their health, to determine whether in utero TCDD exposure is associated with health outcomes at birth or later in life. The proposed study will use DNA from blood collected during the current (2014-2016) follow up to genotype mother-child pairs in the aryl hydrocarbon receptor (gene: AhR, protein: AhR) pathway, an enzymatic network that directs the metabolism of TCDD and other xenobiotics in humans. We will conduct a gene-by- environment (GxE) analysis to evaluate the modifying effect of genetic polymorphisms in the AhR pathway on susceptibility to dioxin toxicity in women and their children born after the explosion. In particular, we will use longitudinal measurements of serum TCDD (1976 and 1996) to examine differences in TCDD metabolism across genetic subgroups of the SWHS (Aim 1). We will then use genotype data on mother-child pairs in AhR pathway genes to examine interaction between the maternal and child genotypes with in utero dioxin exposure on birthweight in children born after the explosion. With its targeted focus on the AhR pathway, this study is uniquely equipped to examine the influence of genotype on dioxin half-life longitudinally and the first study of how both maternal and child genetics may shape fetal susceptibilities to dioxin.